| Obesity has become a worldwide epidemic,and the trend is becoming increasingly serious.It is an independent risk factor for metabolic syndrome;major medical problems associated with the development of hypertension,type 2 diabetes(T2DM),dyslipidemia and respiratory disorders;and ultimately life-threatening cardiovascular disease(CVD),stroke,and certain types of cancer.The current estimates suggest that there are nearly 2.1 billion people in the world who are either overweight or obese.Overweight and obesity are the fifth leading cause of death in the world and at least 2.8 million deaths worldwide each year.In a word,obesity is a worldwide epidemic associated with increased mortality and a significant burden to health care systems worldwide.Mitochondrial function in white adipocytes determines lipid homeostasis and insulin sensitivity.It directly regulates glucose and fatty acid oxidation,and also impacts other metabolic pathways,such as lipogenesis,lipolysis and FA re-esterification.Altered lipid metabolism and mitochondrial activity promote accumulation of triglycerides in white adipose tissues(WATs),liver and muscle,which eventually lead to the occurrence of obesity.Mitochondrial dysfunction in adipocytes leads to the production of toxic lipid species,inflammation and insulin resistance.A recent study has revealed defective mitochondrial biogenesis and oxidative metabolic pathways in white adipose tissues during acquired obesity,preceding the metabolic disturbances in obesity.Moreover,White adipocytes are poor in mitochondria and have a low oxidative capacity.Thus,enhancing mitochondrial biogenesis and fatty acid oxidative capacity could lead to reduce lipid storage of white adipocytes and decreased release of free fatty acids from adipocytes.It has been proposed as a potential therapeutic target for the management of obesity and related metabolic disorders.Moreover,mitochondrion is a key organelle responsible for substrate oxidation and energy dissipation,which are considered the main quantitative source of free radicals in cells.And,the respiratory chain generates ROS(reactive oxygen species)even in healthy mitochondria.Actually,ROS are relatively short-lived molecules that exert local effects.In the physiological state,mitochondrial ROS are detoxified into water,and only a small amount of residual of ROS persists.ROS production in moderation may,serve to maintain cellular homeostasis by creating a tolerable oxidative environment without inflicting cellular damage.However,chronic sustained increases in ROS may be deleterious,giving rise to oxidative stress and causing cellular damage.PGC-1α is a major regulator of mitochondrial biogenesis.PPAR γcoactivator-1α(PGC-1α)controls the activity of several transcription factors involved in mitochondrial biogenesis including NRF-1,NRF-2 and Tfam.Activation of Mitochondria biogenesis is required for the increased metabolic and energy demands during the recovery phase of acute organ injury.In addition to its activation of mitochondrial biogenesis,PGC-1α can also up-regulate genes of the mitochondrial fatty acid oxidation pathway,such as UCP1 and CPT1.Vanin-1 acts as a sensor of oxidative stress whose gene expression is reportedly upregulated by oxidative stress through 2 antioxidant response-like elements.Vanin-1 is a membrane-anchored pantetheinase primarily expressed in kidney epithelia,intestine and liver.It hydrolyzes pantetheine to pantothenic acid(vitamin B5)and the low-molecular-weight thiol cysteamine,a potent endogenous antioxidant.Vanin-1 deficient mice show better resistance to oxidative injury.This protection is associated with increased γ-glutamylcysteine synthetase activity and increased stores of reduced glutathione.In addition,Vanin-1 has recently gained attention as a novel modulator of glucose-and lipid metabolism,and has been suggested as a potential target to treat metabolic diseases.Especially under fasting conditions,Vanin-1 expression appears to prevent excessive accumulation of TG in the liver.Interestingly,pantethine,the stable disulfide of pantetheine and substrate for Vanin activity,is known as a natural compound with hypolipidemic effects.These studies clearly raise the possibility of an association among Vanin-1,mitochondrial function and lipid metabolism.However,the role of Vanin-1 in lipid metabolism is still known less,especially in the adipose tissues.Moreover,there is no evidence about Vanin-1 ability to regulate these mitochondrial function such as mitochondrial biogenesis and fatty acid oxidation in white adipose tissues.According to this scientific problem,we carried out related researches by mice epididymal WATs.Our results showed that Vanin-1 mRNA and protein levels in the WATs of mitochondrial dysfunction mice models were down-regulated.Conversely,the expression levels of Vanin-1 were upregulated in the WATs of mitochondrial activation mice models.This implies that Vanin-1 is positively correlation with mitochondrial function.Next,in vivo,we demonstrated that Vanin-1 knockout mice were presented more weight gain,fat mass and impaired insulin sensitivity compared with wild type(WT)controls.In particular,mitochondrial DNA content was significantly reduced in white adipose tissues of Vanin-1 KO mice compared with WT mice,as a result of the decreased mitochondrial biogenesis in WAT.This was accompanied by an decrease in gene expression of Cpt1,Ucpl and Pgc-1α,which are related to fatty acid oxidation.But,overexpression of Vanin-1 in the WAT of mice completely reversed these results.In vitro experiments showed that adenovirus-mediated Vanin-1 overexpression can specifically increase the content of mitochondrial DNA,stimulate the genes expression involved in mitochondrial biogenesis and fatty acid oxidation,such as Pgc-1α,Nrf,Tfam,Ucpl and Cpt1,which are consistent with the reduction of lipid accumulation in the mature HPAs(human preadipocytes).On the contrary,knockdown of Vanin-1 reversed FSK-induced decrease of fat storage in the HPAs.And,interference Vanin-1 expression inhibited FSK-stimulated the increase of mitochondrial DNA content in the HPAs.More importantly,the inhibitory effects of Vanin-1 deficiency on FSK-induced mitochondrial biogenesis and fatty asids oxidatiion related genes(such as PGC-1α,Tfam,Nrf1,Ucpl,Cpt1)activation in HPAs.In general,this study aimed to investigate the potential role of Vanin-1 in the regulation of mitochondrial function and related signaling pathways in WATs,and summarizes the results from phenotypic changes to related genes alteration.All these findings are compatible with the hypothesis that vanin-1 can lose weight,reduce the excessive accumulation of lipid and improve insulin sensitivity by promoting mitochondrial biogenesis,mtDNA content and fatty acids oxidation in eWATs.We show for the first time the relationship between Vanin-1 and mitochondrial function in eWATs,enrich its functions in the regulation of lipid metabolism.These will provide theoretical basis for study systematically mitochondrial function related fatty acids metabolic disorders,also provide a regulation target to treat metabolic diseases. |
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